Aquaporin‐3 deficiency slows cyst enlargement in experimental mouse models of autosomal dominant polycystic kidney disease. Issue 5 (15th February 2019)

• Record Type: Journal Article
• Authors: Wang, Weiling; Geng, Xiaoqiang; Lei, Lei; Jia, Yingli; Li, Yingjie; Zhou, Hong; Verkman, Alan S.; Yang, Baoxue
• Is Part Of: FASEB journal. Volume 33:Issue 5(2019)
• Page Start: 6185
• Page End: 6196
• Publication Date: 2019-02-15
• Subjects: water channel -- ADPKD -- glucose metabolism -- AMPK/mTOR signaling -- HIF1‐α; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201801338RRR
• Languages: English
• ISSNs: 0892-6638

Abstract

ABSTRACT: Human autosomal dominant polycystic kidney disease (ADPKD) is characterized by bilateral renal cysts that lead to a decline in kidney function. Previous studies reported aquaporin (AQP)‐3 expression in cysts derived from collecting ducts in ADPKD. To study the role of AQP3 in cyst development, we generated 2 polycystic kidney disease (PKD) mouse models: kidney‐specific Pkd1 knockout mice and inducible Pkd1 knockout mice, each without and with AQP3 deletion. In both models, kidney sizes and cyst indexes were significantly reduced in AQP3‐null PKD mice compared with AQP3‐expressing PKD mice, with the difference seen mainly in collecting duct cysts. AQP3‐deficient kidneys showed significantly reduced ATP content, increased phosphorylated (p)‐AMPK, and decreased p‐ERK and p‐mammalian target of rapamycin (mTOR). In a matrix‐grown Madin‐Darby canine kidney cyst model, AQP3 expression promoted cyst enlargement and was associated with increased expression of hypoxia‐inducible factor 1‐ α and glucose transporter 1 and increased glucose uptake. Our data suggest that the slowed renal cyst enlargement in AQP3 deficiency involves impaired energy metabolism in the kidney through AMPK and mTOR signaling and impaired cellular glucose uptake. These findings implicate AQP3 as a novel determinant of renal cyst enlargement and hence a potential drug target in ADPKD.—Wang, W., Geng, X., Lei, L., Jia, Y., Li, Y., Zhou, H., Verkman, A. S., Yang, B. Aquaporin‐3 deficiency slows cyst enlargement in experimental mouse models of autosomal dominant polycystic kidney disease. FASEB J. 33, 6185–6196 (2019). www.fasebj.org